Project Summary Cataract, the clouding of the eye lens is responsible for 48% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataract in the world. Cataract is easily treated by surgery and is considered as one of the most cost-effective interventions. Although cataract surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataract, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataract. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataract formation by 10 years can reduce the vision care expense by 50%. In addition, our preliminary data supports the hypothesis that drug-like synthetic small molecules representing the CAP01023 series specifically increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. Therefore, the basic goal of our proposal is to discover potent small molecule activators of AAC to be developed into safe and cost-effective non-surgical treatment to delay and/or reverse cataract related blindness, and the specific aims are: (Aim 1) Structure based design, commercial acquisition and synthesis of small molecule activators of AAC; (Aim 2) Assess therapeutic efficacy of AAC activators from Specific Aim 1 using in vitro glycation and ex-vivo cell culture experiments and (Aim 3). Assess compounds from Specific Aim 2 for preliminary in vivo safety and efficacy using ex vivo organ culture cataract models. The milestone for the Phase I studies is to discover 2-4 potent activators of AAC with EC50 ? 50uM, shown to be safe in rabbit eye lens, maintain clarification of lens for ?12 days in organ culture experiments with concomitant compound uptake and decrease in aggregated forms of lenticular client protein levels.